The present invention is directed to compositions and methods for making bone graft substitutes. More specifically, the present invention is directed to manufacturing a bone graft substitute (BGS) by powder compaction.
Bone graft is used to fill spaces in bone tissue that are the result of trauma, disease degeneration or other loss of tissue. Clinicians perform bone graft procedures for a variety of reasons, often to fill a bone void created by a loss of bone or compaction of cancellous bone. In many instances, the clinician also must rely on the bone graft material to provide some mechanical support, as in the case of subchondral bone replacement or compaction grafting around total joint replacement devices. In these instances, clinicians pack the material into the defect to create a stable platform to support the surrounding tissue and hardware.
There are several options available to the orthopaedic clinician for bone graft material. Most commonly, the source of the graft material is either the patient (autograft), which is clinically preferable, or a donor (allograft). However, autograft has the potential drawback of increased pain and morbidity associated with a second surgical procedure, in addition to having a limited supply of the bone. In autograft and, to a lesser extent, in allograft there are biological factors such as proteins or cells that are present that can assist in the fracture healing process. Xenografts and bone graft substitutes are other options.
Moreover, synthetically derived substitute material has advantages over human derived bone graft and naturally derived substitutes, including: 1) more control over product consistency; 2) less risk for infection and disease; 3) no morbidity or pain caused by harvesting of the patient""s own bone for graft; and 4) availability of the substitute in many different volumes (that is, it is not limited by harvest site of the patient).
The BGS materials that have been used commercially exhibit various levels of bioactivity and various rates of dissolution. BGS products are currently available in several forms: powder, gel, slurry/putty, tablet, chips, morsels, and pellet, in addition to shaped products (sticks, sheets, and blocks). In many instances, the form of BGS products is dictated by the material from which they are made. Synthetic materials (such as calcium sulfates or calcium phosphates) have been processed into several shapes (tablets, beads, pellets, sticks, sheets, and blocks) and may contain additives such as antibiotics (e.g., Osteoset(copyright)-T (Wright Medical Technology; Arlington, Tenn.)) or bioactive agents (e.g., Rhakoss(copyright) (Orthovita(copyright); Malvern, Pa.)). Allograft products, in which the source of the bone graft material is a donor, are typically available as chips and can be mixed with a gel to form a composite gel or putty. None of the current products and technologies offered for BGS is capable of offering an allograft granule or shape for easy delivery and scaffold structure, in addition to being conformable to the surgical site. Furthermore, none but one (Osteoset(copyright)-T) of the current products and technologies offered for BGS is capable of offering an allograft or synthetic granule or shape containing a bioactive agent or agents, such as an antibiotic or bone morphogenetic proteins.
Past solutions to produce BGS products have included gel, putty, paste, formable strips, blocks, granules, chips, pellets, tablets, and powder. A skilled artisan recognizes there are multiple references directed to bone graft substitutes, including Medica Data International, Inc., Report #RP-591149, Chapter 3: Applications for Bone Replacement Biomaterials and Biological Bone Growth Factors (2000) and Orthopaedic Network News, Vol. 11, No 4, October 2000, pp. 8-10.
To date, DBM products have been produced in chips, granules, gel, or putty forms only. No solid DBM product (as opposed to a putty) which has undergone a shaping process is currently available to the health care provider. It is a disadvantage of the presently available products to have no shape which is interlocking, and the irregularly-shaped chips of presently available products do not compact sufficiently and also fail to generate reproducible results. Other calcium sulfate-based products have been made using a casting or molding process, as opposed to a dry powder compaction process of the present invention. Osteoset(copyright)-T pellets are likely to have been tableted because of their simple shape. A more complicated shape that could provide improved interlocking between the granules over the tableting process used in the art requires the use of a more advanced manufacturing process. The manufacturing of JAX(trademark) (Smith+Nephew, Inc.; Memphis, Tenn.) bone void filler requires the use of a powder compaction process to be able to produce the advanced interlocking granule shape.
U.S. Pat. Nos. 6,030,636; 5,807,567; and 5,614,206 are directed to calcium sulfate controlled release matrix. They provide forming a pellet prepared by the process comprising mixing powder consisting essentially of alpha-calcium sulfate hemihydrate, a solution comprising water, and, optionally, an additive and a powder consisting essentially of beta-calcium sulfate hemihydrate to form a mixture, and forming the mixture into the pellet. The pellets were formed by pouring a slurry mixture of the desired components into cylindrical molds.
U.S. Pat. Nos. 5,569,308 and 5,366,507 regard methods for use in bone tissue regeneration utilizing a conventional graft material/barrier material layered scheme. The barrier material is a paste formed immediately prior to its use by mixing calcium sulfate powder with any biocompatible, sterile liquid, whereas the graft material is also a paste form comprised of a mixture of water and at least autogenous cancellous bone, DFDBA, autogenous cortical bone chips, or hydroxylapatite.
U.S. Pat. No. 4,619,655 is directed to Plaster of Paris as a bioresorbable scaffold in implants for bone repair. The inventors provide an animal implant composed of a binder lattice or scaffold of Plaster of Paris and a non-bioresorbable calcium material such as calcium phosphate ceramic particles and, in a specific embodiment, the implant may contain an active medicament bound within the plaster. The implant composition of the invention may be preformed into the desired shape or shapes or it may be made up as a dry mix which can be moistened with water just prior to use to provide a fluid or semisolid, injectable formulation which can be injected into the appropriate body space as required for bone reconstruction.
U.S. Pat. No. 4,384,834 is directed to devices for compacting powder into a solid body, comprising a compaction chamber, a moveable support for the powder which extends into the compaction chamber, and means for launching a punch against the powder to form the solid body. The compaction chamber is formed by a block having a conical bore and a conical sleeve having a continuous uncut sidewall moveable within the conical bore to be radially compressed thereby.
U.S. Pat. No. 5,449,481 concerns apparatus and methods for producing a powder compact comprising loading a rubber mold having a cavity shaped according to a desired configuration of the powder compact into a recess formed by a die, in addition to a lower punch inserted into the die. The method steps include filling a cavity of the rubber mold with powder, placing an upper punch in contact with an opposing surface of the die, and pressing the rubber mold filled with powder in a space formed by the die, the lower punch and the upper punch. In specific embodiments, the upper or lower punches are secured.
U.S. Pat. No. 5,762,978 is directed to a batching device having a series of die holes which are fed powder or granular material, upper and lower punches for each die hole, wherein the punches have counterfacing respective working heads, in addition to a rotary turret comprising the die holes, and driving means for adjusting distances between the working heads of the punches. The driving means includes a driving cam for at least one of the punches and filling operation cam means.
U.S. Pat. No. 6,106,267 regards tooling for a press for making an ingestible compression molded product, such as a tablet, from a granular feedstock material wherein the tooling comprises a die having a cylindrical die cavity and an open end for introducing the feedstock, and first and second punches with end faces which compress the feedstock material and which thereby would form the product whose surfaces conform to the end faces of the punches. The tip portion of the first punch is formed of an elastically deformable material so as to undergo deformation upon compression of the feedstock and which includes a wiping ring for wiping the inner surface of the die cavity upon movement of the punch within the die.
U.S. Pat. No. 5,603,880 concerns methods and an apparatus for manufacturing tablets. Plastic polymer film is pressed to form receptacles and filled with a predetermined amount of a powder under a pressurized condition.
U.S. Pat. No. 6,177,125 regards methods for manufacturing coated tablets from tablet cores and coating granulate using a press having at least one compression chamber and a feed device for tablet cores, comprising adding a pasty tablet core to the coating granulate to be compressed and compressing the coating granulate and the tablet cores simultaneously in a single pressing step.
U.S. Pat. No. 5,654,003 is directed to methods of making a solid comestible by forming deformable particles in size from 150 to 2000 microns wherein the particles are compressible in a die and punch tableting machine by subjecting a feedstock comprising a sugar carrier material, wherein the compressed product possesses a rigid structure and has a hard surface which resists penetration and deformation.
U.S. Pat. No. 5,017,122 regards a rotary tablet press for molding tablets through compression of powders and granules having a plurality of dies which rotate around a central axis, multiple upper and lower punches rotatable with the dies, and means for introducing electrically charged lubricant particles onto the tablets.
U.S. Pat. No. 5,158,728 is directed to an apparatus for forming a two-layer tablet having a die table comprising multiple die stations, each die having a cylindrical cavity. The upper punch and lower punch has at least one insert sized and positioned on the upper punch means and lower punch means, respectively, to fit within the die cavity on the die on die table.
Thus, presently available compositions and methods in the art provide no bone graft substitute particles having consistent shapes and whose shapes interrelate in a manner to impart a three-dimensional structure for strength and bone ingrowth. The present invention supplies a long-sought solution in the art by making BGS products or granules, such as demineralized bone matrix, by powder compaction to provide a scaffold structure for ingrowth from the host bone and for the purpose of easy delivery.
An object of the present invention is to manufacture a BGS shape by compressing or compacting powder or powders; more specifically, by powder compaction, which is a process used primarily in metal and ceramic powder processing.
Another object of the present invention is to use powder compaction to manufacture an allograft (human bone, DBM) bone graft substitute shape.
An additional object of the present invention is to utilize powder compaction to produce a synthetic or ceramic (such as calcium sulfate or calcium phosphate) bone graft substitute shape.
Another object of the present invention is to use powder compaction to produce an allograft, synthetic or ceramic bone graft substitute shape containing bioactive agents (such as antibiotic, BMPs, acids, angiogenic agents and the like).
An additional object of the present invention is to use powder compaction to produce an allograft/synthetic or ceramic composite bone graft substitute shape.
Another object of the present invention is to use powder compaction to produce an allograft/synthetic or ceramic composite bone graft substitute shape containing bioactive agents.
An additional object of the present invention is to use a processing aid (such as stearic acid, magnesium stearate, calcium stearate) or a mix of two or more of these processing aids to produce a JAX(trademark) shape, tablet, or other shape known in the art.
An object of the present invention is a method of manufacturing a shaped bone graft substitute comprising the step of compressing a granulated bone material into the shape. In a specific embodiment, the bone material is an allograft material, a ceramic material, a polymer or combinations thereof. In another specific embodiment, the material further comprises a processing aid composition. In an additional specific embodiment, the processing aid composition is selected from the group consisting of stearic acid, calcium stearate, magnesium stearate, natural polymer, synthetic polymer, sugar and combinations thereof. In a further specific embodiment, the natural polymer is starch, gelatin, or combinations thereof. In another specific embodiment, the synthetic polymer is methylcellulose, sodium carboxymethylcellulose, or hydropropylmethylcellulose. In a further specific embodiment, the sugar is glucose or glycerol. In an additional specific embodiment, the allograft bone material is cortical-cancellous bone. In another specific embodiment, the allograft bone material is demineralized bone matrix. In a further specific embodiment, the shape is a three-dimensional intricate shape. In another specific embodiment, the shape is selected from the group consisting of a jack, a tablet, a strip, a block, a cube, a chip, a pellet, a pill, a lozenge, a sphere, a ring, and combinations thereof In another specific embodiment, the shape is a JAX(trademark) particle. In a further specific embodiment, the shape is a jack, a JAX(trademark), or a ring. In another specific embodiment, the ceramic material is selected from the group consisting of hydroxylapatite, calcium sulphate, alumina, silica, calcium carbonate, calcium phosphate, calcium tartarate, bioactive glass, and combinations thereof. In another specific embodiment, the substitute further comprises a biological agent. In an additional specific embodiment, the biological agent is added to the material prior to the compaction step. In another specific embodiment, the biological agent is added to the bone graft substitute subsequent to the compaction step. In another specific embodiment, the agent is selected from the group consisting of a growth factor, an antibiotic, a strontium salt, a fluoride salt, a magnesium salt, a sodium salt, a bone morphogenetic factor, a chemotherapeutic agent, a pain killer, a bisphosphonate, a bone growth agent, an angiogenic factor, and combinations thereof. In an additional specific embodiment, the growth factor is selected from the group consisting of platelet derived growth factor (PDGF), transforming growth factor b (TGF-b), insulin-related growth factor-I (IGF-I), insulin-related growth factor-II (IGF-II), fibroblast growth factor (FGF), beta-2-microglobulin (BDGF II), bone morphogenetic protein (BMP), and combinations thereof. In an additional specific embodiment, the antibiotic is selected from the group consisting of tetracycline hydrochloride, vancomycin, cephalosporins, and aminoglycocides such as tobramycin, gentamicin, and combinations thereof. In another specific embodiment, the factor is selected from the group consisting of proteins of demineralized bone, demineralized bone matrix (DBM), bone protein (BP), bone morphogenetic protein (BMP), osteonectin, osteocalcin, osteogenin, and combinations thereof. In an additional specific embodiment, the agent is selected from the group consisting of cis-platinum, ifosfamide, methotrexate, doxorubicin hydrochloride, and combinations thereof. In a further specific embodiment, the pain killer is selected from the group consisting of lidocaine hydrochloride, bipivacaine hydrochloride, non-steroidal anti-inflammatory drugs such as ketorolac tromethamine, and combinations thereof. In another specific embodiment, the particles of the material are less than about 10 millimeters in diameter. In a further specific embodiment, the particles of the material are less than about 250xcexcm in diameter. In another specific embodiment, the particles of the material are in a range of about 50 to 180 microns.
In an additional object of the present invention, there is a method of manufacturing a bone graft substitute comprising the steps of obtaining a bone material; pulverizing the material to produce a granulated bone material; and subjecting the granulated bone material to a powder compaction process. In a specific embodiment, the powder compaction process utilizes a withdrawal press, wherein the press comprises a stationary lower punch; a moveable die; a moveable upper punch; and a moveable lower punch, wherein the stationary lower punch is contained within the moveable lower punch. In a specific embodiment, the powder compaction process utilizes a withdrawal press, wherein the press comprises a stationary lower punch; a moveable lower punch, wherein the stationary lower punch is contained within the moveable lower punch; a stationary upper punch; a moveable upper punch, wherein the stationary upper punch is contained within the moveable lower punch; and a moveable die.
In another object of the present invention there is a method of manufacturing a shaped bone graft substitute from granulated bone material, the method comprising the steps of providing a stationary lower punch and a moveable lower punch which is vertically moveable about the stationary lower punch, a moveable die having at least one cavity and positionable generally above the stationary lower punch, and a moveable upper punch; introducing the granulated bone material into the cavity; positioning the moveable die generally above the stationary lower punch; moving the moveable upper punch to pressably contact the powder in opposition to the moveable lower punch and stationary lower punch; and moving the moveable lower punch to pressably contact the powder in opposition to the moveable upper punch, whereby the moving steps form the material into the shaped bone graft substitute. In a specific embodiment, the steps of moving the upper and lower punches effect a substantially uniform distribution of pressure within the material. In another specific embodiment, the punches are configured such that the shape of the bone graft substitute resulting from the moving steps is a shape selected from the group consisting of a JAX(trademark) particle, a jack, a tablet, a strip, a block, a cube, a pellet, a pill, a lozenge, a sphere, and a ring. In a further specific embodiment, at least one of the moving steps applies a force to the material in a range of about 0.2 to about 5 tons. In another specific embodiment, at least one of the moving steps applies a force to the material in a range of about 0.2 to about 2 tons. In an additional specific embodiment, at least one of the moving steps applies a force to the material in a range of about 0.5 to about 1 ton. In another specific embodiment, the moving step of the moveable lower punch to the material is subsequent to the moving step of the moveable upper punch to the material.
In another object of the present invention there is a method of manufacturing a shaped bone graft substitute from granulated bone material, the method comprising the steps of introducing an amount of the granulated bone material into the cavity; providing a lower punch assembly, an upper punch assembly, and a moveable die positionable generally above the lower punch assembly; positioning the moveable die generally above the lower punch assembly; moving the lower punch assembly in opposition to the moveable upper punch to pressably contact the material; moving the upper punch assembly in opposition to the moveable lower punch to pressably contact the material, whereby the moving steps form the material into the shaped bone graft substitute. In a specific embodiment, the lower punch assembly is comprised of at least one of a stationary lower punch and a moveable lower punch vertically moveable about the stationary lower punch. In another specific embodiment, the upper punch assembly is comprised of at least one of a stationary upper punch and a moveable upper punch vertically moveable about the stationary upper punch.
In an additional specific embodiment of the present invention there is an apparatus for shaping a bone graft substitute from granulated bone material, the apparatus comprising a stationary lower punch having a top surface; a moveable lower punch vertically moveable about the stationary lower punch and having a top surface; a moveable die having at least one cavity and positionable generally above the stationary lower punch; and a moveable upper punch, such that the moveable upper punch moves in opposition to the moveable lower punch to pressably contact the material contained within the cavity, whereupon following pressably contacting the material by the moveable lower punch the top surface height of the lower moveable punch is above the top surface height of the stationary lower punch.
In an additional embodiment of the present invention, there is a method for manufacturing a bone graft substitute from granulated bone material, the method comprising the steps of providing a first punch assembly having a first contact surface configured to effect a relief profile onto a first surface of the granulated bone material; a second punch assembly having a second contact surface; and a moveable die having at least one cavity; introducing the bone material into the cavity; positioning the moveable die generally in alignment with the first punch assembly; moving at least a portion of the first punch assembly to pressably contact the material in opposition to the second punch assembly to effect the desired relief profile on the first surface thereof; and moving at least a portion of the second punch assembly to pressably contact the material in opposition to the first punch assembly, whereby the moving steps form the material into the shaped bone graft substitute.
In another object of the present invention, there is a method for manufacturing a bone graft substitute from demineralized bone matrix material, the method comprising the steps of providing a first punch assembly having a first contact surface configured to effect a relief profile onto a first surface of the demineralized bone matrix material; a second punch assembly having a second contact surface; and a moveable die having at least one cavity; introducing the demineralized bone matrix material into the cavity; positioning the moveable die generally in alignment with the first punch assembly; moving at least a portion of the first punch assembly to pressably contact the material in opposition to the second punch assembly to effect the desired relief profile on the first surface thereof; and moving at least a portion of the second punch assembly to pressably contact the material in opposition to the first punch assembly, whereby the moving steps form the material into the shaped bone graft substitute. In a specific embodiment of the present invention, the contact surface area of the first punch assembly is generally equivalent to a contact surface area of the second punch assembly such that the moving steps apply a substantially uniform pressure distribution to the material. In another specific embodiment, the first punch assembly includes a stationary punch and a moveable punch, such that the steps of moving the first punch assembly includes moving the moveable punch to pressably contact the material. In a further specific embodiment, the second punch assembly includes a stationary punch and a moveable punch, such that the steps of moving the first punch assembly includes moving the moveable punch to pressably contact the material.
In an object of the present invention there is an apparatus for manufacturing a bone graft substitute from a granulated bone material, the apparatus comprising a first punch assembly having a first contact surface having a profile configured to effect a relief profile onto a surface of the bone material; a second punch assembly having a second contact surface, the second contact surface positioned in general alignment with the first contact surface; and a moveable die having at least one cavity, the moveable die being positionable generally in between the first and second punch assemblies.
Other and further objects, features and advantages would be apparent and eventually more readily understood by reading the following specification and by reference to the company drawing forming a part thereof, or any examples of the presently preferred embodiments of the invention are given for the purpose of the disclosure.